Nanosuspensions have emerged as a promising strategy for an efficient delivery of hydrophobic drugs because of their versatile features such as very small particle size. Methods such as media milling and high-pressure homogenization have been used commercially for producing nanosuspensions [V. B. Patravale, A. A. Date, R. M. Kulkarni, Journal of Pharmacy and Pharmacology, Vol. 56, No. 7, pages 827 (2004)]. The engineering of nanosuspensions employing emulsions and microemulsions as templates has been addressed in the above literature. The unique features of nanosuspensions have enabled their use in various dosage forms, including specialized delivery systems such as mucoadhesive hydrogels. Rapid strides have been made in the delivery of nanosuspensions by parenteral, peroral, ocular and pulmonary routes. Currently, efforts are being directed to extending their applications in site-specific drug delivery.
The ability to produce the nanoparticles of desired size with great precision (narrow size distribution and small variation) is the key factor of producing the nanosuspensions. The process of producing nanoparticles can be catagorised by two approaches:                The Top-Down approach—where one starts with the bulk material and machines it, way down to the nano-scale, and        The Bottom-Up approach, starting at the molecular level and building up the material through the small cluster level to the nanoparticle and finally the assembly of nanoparticles.Theory of Cavitation        
Cavitation is the phenomenon of sequential formation, growth and collapse of millions of microscopic vapour bubbles (voids) in the liquid. The collapse or implosion of these cavities creates high localized temperatures roughly of 14000 K and a pressure of about 10000 atm or results into short-lived, localized hot-spot in cold liquid. Thus, cavitation serves as a means of concentrating the diffused fluid energy locally and in very short duration, creating a zone of intense energy dissipation [Suslic K. S., J. J., Gawlenowski, P. F. Schubert and H. H. Wang, J. Phy. Chem. 87, 2299 (1983)].
Acoustic Cavitation
Cavitation is induced by passing high frequency (16 kHz-100 MHz) sound waves i.e., ultrasound through liquid media. When ultrasound passed through the liquid media, in the rarefaction region local pressure falls below the threshold pressure for the cavitation (usually the vapour pressure of the medium at the operating temperature), millions of the cavities are generated. In the compression region the pressure in the fluid rises and these cavities are collapsed. The collapse conditions are dependent on the intensity and frequency of the ultrasound as well as liquid physical properties, temperature of the liquid and the dissolves gases [J. P. Lorimer and T. J. Mason, Chem. Soc. Rev. 16, 239-274 (1987)].
Hydrodynamic Cavitation
Hydrodynamic cavitation can simply be generated by the passage of the liquid through a specified geometry of constriction such as orifice plates, ventury etc. When the liquid passes through the constriction, the kinetic energy of the liquid increases at an expense of the pressure. If the throttling is sufficient to cause the pressure around the point of vena contracta to fall below the threshold pressure for the cavitation (usually the vapour pressure of the medium at the operating temperature) millions of the cavities are generated. Subsequently, as the liquid jet expands, the pressure recovers and this results in the collapse of the cavities releasing the energy in the form of a high magnitude pressure pulse. During the passage of the liquid through the constriction, the boundary layer separation occurs and substantial amount of the energy is lost in the form of turbulence and permanent pressure drop [P. R. Gogate and A. B. Pandit, Rev. in Chem. Engg. 17(1), 2001, 1-85].
Very high intensity of the turbulence, downstream side of the constriction is generated and its intensity depends on the magnitude of the permanent pressure drop, which again depends on the geometry of the constriction and the flow conditions in the liquid. The intensity of the turbulence has a profound effect on the cavitation activity and the intensity as shown by Moholkar and Pandit [V. S. Moholkar and A. B. Pandit, AICHE J. 43 (6) 1997, 1641-1648]. A dimensionless number known as cavitation number (Cv) is used to relate the flow conditions with the cavitation intensity as follows,
                    Cv        =                                            P              2                        -                          P              v                                                          1              2                        ⁢            ρ            ⁢                                                  ⁢                          V              o              2                                                          Eq        ⁢                                  ⁢                  (          1          )                    where P2 is the recovered downstream pressure; Pv is the vapour pressure of the liquid and Vo is the liquid velocity at the orifice. The cavitation number at which the inception of cavitation occurs is known as the cavitation inception number Cvi. Ideally speaking, the cavitation inception should occur at 1.0. But Harrison and Pandit [S. T. L. Harrison and A. B. Pandit, Proceedings of 9th Int. Biotech. Symp., Washington, USA 1992] have reported that, generally the inception of the cavitation occurs from 1.0-2.5. This has been attributed to the presence of the dissolved gases in the flowing liquid. Yan and Thorpe [Y. Yan and R. B. Thorpe, International Journal of Multiphase Flow, Volume 16, Issue 6, November-December 1990, Pages 1023-1045.] have shown that Cv is a function of the flow geometry and usually increases with an increase in the size of the opening in a constriction such as an orifice in a flow.
Advantages of hydrodynamic cavitation over acoustic cavitation have been reported as follows [P Senthilkumar, M. Chem. Engg. Thesis, MUICT, Mumbai, 1997]:                It is one of the cheapest and energy efficient methods of generating cavitation.        The equipment used for generating cavitation is simple.        The scale up of the system is relatively easy.Theory of Size Reduction:        
To reduce a material's particle size, large particles or lumps must be fractured into smaller particles. To initiate fractures, external forces are applied to the particles. Generally, the extent of particle size reduction caused by an external force depends on the amount of energy supplied to the particle, the rate at which it's supplied, and the manner in which it's supplied. The application of size-reduction forces can be broken into the following four categories [S. Wennerstrum, T. Kendrick, J. Tomaka, and J. Cain, Powder and Bulk Engineering, January 2005, pp 1-5].    Impact milling: Impact milling occurs when a hard object that applies a force across a wide area, hits a particle with a certain momentum to fracture it. The least size obtained by an impact mills is of the order of 50 microns for mechanical impact mills and less than 10 microns for fluid jet mills [S. Wennerstrum, T. Kendrick J. Tomaka, and J. Cain, Powder and Bulk Engineering, January 2005, pp 1-5].    Attrition milling: In attrition milling, non erodable grinding media continuously contact the material to be ground, systematically grinding its edges down. Attrition mills can reduce 1000 micron (20 mesh) particles of friable materials such as chemicals and minerals down to less than 1 micron. One such type is the media mill (also called a ball mill) [S. Wennerstrum, T. Kendrick, J. Tomaka, and J. Cain, Powder and Bulk Engineering, January 2005, pp 1-5].    Knife milling: In knife milling, a sharp blade applies high, head-on localised shear force to a large particle, cutting it to a predetermined size to create smaller particles and minimize fines. Knife mills can reduce 2 inch or larger chunks or slabs of material, including elastic or heat-sensitive materials down to 250 to 1,200 microns [S. Wennerstrum, T. Kendrick, J. Tomaka, and J. Cain, Powder and Bulk Engineering, January 2005, pp 1-5].    Direct pressure milling: Direct pressure milling occurs when a particle is crushed or pinched between two hardened surfaces. Direct-pressure mills typically reduce 1-inch or larger chunks of friable materials down to 800 to 1,000 microns.
Most mills use a combination of these principles to apply more than one type of force to the particle to be ground. The very important part is to choose the best type of size reduction mode based on the characteristics of the material to be processed and initial and final size requirements.
The physical properties of the material to be reduced are also important to decide the method and the equipment to be used for reducing it. Nonfriable materials such as polymers, resins, waxes, and rubber can't be shattered or fractured using regular impact or direct-pressure milling. Knife milling often cannot reduce a nonfriable material to a very fine particle size range. Typical methods, for reducing nonfriable materials require turning the nonfriable material into a friable material by freezing it below glass transition temperature. In certain cases, preconditioning or exposing the particles to a cryogen may be necessary. For low temperature milling with cryogens, care of the components of the equipment is very important as they also become brittle and certain lubricating greases lose their viscosity and freeze [9].
Use of Cavitation in Nanotechnology:
The extreme transient conditions generated in the vicinity and within the collapsing cavitational bubbles have been used for the size reduction of the material to the nano scale. Nanoparticles synthesis techniques include sonochemical processing, cavitation processing, and high-energy ball milling. In sonochemistry, an acoustic cavitation process can generate a transient localized hot zone with extremely high temperature gradient and pressure [K. S. Suslick, T. W. Hyeon, M. W. Fang, Chem Mater. 8 (1996) 2172]. Such sudden changes in temperature and pressure assist the destruction of the sonochemical precursor (e.g., organometallic solution) and the formation of nanoparticles. The technique in principle can be used to produce a large volume of material for industrial applications but no reports are available in the open literature.
Use of the cavitation for the formation of the Nanoparticles has been reported by Suslick [K. S. Suslick, S. B. Choe, A. A. Cichowlas, M. W. Grinstaff, Nature, 353 (1991) 414]. He sonicated Fe(CO)5 either as a neat liquid or in a decalin solution and obtained 10-20 nm size amorphous iron particles. Similar experiments have been reported for the synthesis of the Nanoparticles of many other inorganic materials using acoustic cavitation [A. Gedanken, Ultrasonics Sonochemistry 11 (2004), pp 47-55]. To understand the mechanism of the formation of the Nanoparticles during the cavitation phenomenon, Hot-Spot theory has been convincingly used. It explains the adiabatic collapse of a bubble, producing the hot spots. This theory claims that very high temperatures (5000-25,000 K) [A. Gedanken, Ultrasonics Sonochemistry 11 (2004), pp 47-55.] are obtained upon the collapse of the bubble. Since this collapse occurs in few microseconds (final adiabatic phase), very high cooling rates, (in excess of 1011 K/s), have been obtained. These high cooling rates hinder the organization and crystallization of the products. For this reason, in all the cases dealing with volatile precursors, where gas phase reactions are predominant, amorphous Nanoparticles have been obtained [A. Gedanken, Ultrasonics Sonochemistry 11 (2004), pp 47-55]. While the explanation for the creation of amorphous products is well understood, the reason for the formation of nanostructured products under cavitation is not yet clear. One possible explanation is that the fast kinetics does not permit the growth of the nuclei, and in each collapsing bubble a few nucleation centers are formed whose growth is limited by the short cavity collapse time. If, on the other hand, the precursor is a non-volatile compound, the reaction occurs in a 200 nm ring surrounding the collapsing bubble [K. S. Suslick, D. A. Hammerton, R. E. Cline, J. Am. Chem. Soc. 108 (1986) 5641]. In this case, the sonochemical reaction occurs in the liquid phase and not inside the collapsing cavity. The products are sometimes nanoamorphous particles, and in other cases, nanocrystalline. This depends on the temperature in the fluid ring region where the reaction takes place. The temperature in this liquid ring is lower than that inside the collapsing bubble, but higher than the temperature of the bulk liquid. Suslick [K. S. Suslick, S. B. Choe, A. A. Cichowlas, M. W. Grinstaff, Nature, 353 (1991) 414] has estimated the temperature in the ring region as around 1900° C. In short, in almost all the sonochemical reactions leading to inorganic products, nanomaterials have been obtained. They vary in size, shape, structure, and in their solid phase (amorphous or crystalline), but they were always of nanometer size. [A. Gedanken, Ultrasonics Sonochemistry 11 (2004), pp 47-55]. Cavitation being a nuclei dominated (statistical in nature) phenomenon, such variations are expected.
In hydrodynamic cavitation, nanoparticles are generated through the creation and release of gas bubbles inside the sol-gel solution [I. E. Sunstrom, IV, W. R. Moser, B. M. Guerts, Chem Mater 8 (1996) 2061]. By rapidly pressurizing in a supercritical drying chamber and exposing it to the cavitational disturbance and high temperature heating, the sol-gel solution is rapidly mixed. The erupting hydrodynamically generated cavitating bubbles are responsible for the nucleation, the growth of the nanoparticles, and also for their quenching to the bulk operating temperature. Particle size can be controlled by adjusting the pressure and the solution retention time in the cavitation chamber. Use of the hydrodynamic cavitation for the same purpose has also reported in some literature. [NanoBioTech News, Vol 3, Number 6, 9 Feb. 2005].
However, none of the literature available reports use of cavitation techniques in the reduction of the size of elastic particulate material to nano levels.